PMC Comprehensive Neuropathies Panel

Associated Conditions
- Charcot-Marie-Tooth DiseaseNeuropathy, Hereditary Sensory And Autonomic, Type Viii
- Congenital Insensitivity To Pain-Hypohidrosis Syndrome
- Hereditary Motor Neuropathy
- Hereditary Sensory and Autonomic Neuropathy
- Small Fiber Neuropathy
- Riboflavin Transporter Deficiency Neuronopathy
- Hereditary Transthyretin-Mediated Amyloidosis
- Spinal Muscular Atrophy
- BAG3-related Charcot-Marie-Tooth disease
- Charcot Marie Tooth disease type 2 (CMT2)
- Charcot-Marie-Tooth disease D (CMTRID)
- Charcot-Marie-Tooth disease type 1A (CMT1A), type 1E (CMT1E), hereditary neuropathy with liability to pressure palsies (HNPP)
- Charcot-Marie-Tooth disease type 1B (CMT1B), type 2I (CMT2I), type 2J (CMT2J), dominant intermediate (DI-CMTD)
- Charcot-Marie-Tooth disease type 1C (CMT1C)
- Charcot-Marie-Tooth disease type 1D (CMT1D), type 3 (CMT3), Dejerine-Sottas syndrome, type 4E (CMT4E), congenital hypomyelinating neuropathy
- Charcot-Marie-Tooth disease type 1F (CMT1F), type 2E (CMT2E)
- Charcot-Marie-Tooth disease type 1G (CMT1G)
- Charcot-Marie-Tooth disease type 1X (CMT1X)
- Charcot-Marie-Tooth disease type 2A (CMT2A), type 6A (CMT6A)
- Charcot-Marie-Tooth disease type 2B (CMT2B)
- Charcot-Marie-Tooth disease type 2B1 (CMT2B1)
- Charcot-Marie-Tooth disease type 2C (CMT2C)
- Charcot-Marie-Tooth disease type 2CC (CMT2CC)
- Charcot-Marie-Tooth disease type 2D (CMT2D)
- Charcot-Marie-Tooth disease type 2DD (CMT2DD)
- Charcot-Marie-Tooth disease type 2F (CMT2F)
- Charcot-Marie-Tooth disease type 2K (CMT2K), type 4A (CMT4A), recessive intermediate A (CMTRIA)
- Charcot-Marie-Tooth disease type 2L (CMT2L)
- Charcot-Marie-Tooth disease type 2M (CMT2M), type B (CMTDIB)
- Charcot-Marie-Tooth disease type 2N (CMT2N)
- Charcot-Marie-Tooth disease type 2O (CMT2O)
- Charcot-Marie-Tooth disease type 2P (CMT2P)
- Charcot-Marie-Tooth disease type 2Q (CMT2Q)
- Charcot-Marie-Tooth disease type 2S (CMT2S)
- Charcot-Marie-Tooth disease type 2T (CMT2T)
- Charcot-Marie-Tooth disease type 2U (CMT2U)
- Charcot-Marie-Tooth disease type 2X (CMT2X)
- Charcot-Marie-Tooth disease type 2Z (CMT2Z)
- Charcot-Marie-Tooth disease type 4 (CMTX4), Cowchock syndrome
- Charcot-Marie-Tooth disease type 4B1 (CMT4B1)
- Charcot-Marie-Tooth disease type 4B2 (CMT4B2)
- Charcot-Marie-Tooth disease type 4B3 (CMT4B3)
- Charcot-Marie-Tooth disease type 4C (CMT4C)
- Charcot-Marie-Tooth disease type 4D (CMT4D)
- Charcot-Marie-Tooth disease type 4F (CMT4F)
- Charcot-Marie-Tooth disease type 4H (CMT4H)
- Charcot-Marie-Tooth disease type 4J (CMT4J)
- Charcot-Marie-Tooth disease type 4K (CMT4K)
- Charcot-Marie-Tooth disease type 5 (CMTX5)
- Charcot-Marie-Tooth disease type 6 (CMTX6)
- Charcot-Marie-Tooth disease type 6B (CMT6B), hereditary motor and sensory neuropathy type VIB (HMSN6B)
- Charcot-Marie-Tooth disease type C (CMTDIC)
- Charcot-Marie-Tooth disease type C (CMTRIC)
- Charcot-Marie-Tooth disease type E (CMT-DIE)
- Charcot-Marie-Tooth disease type F (CMTDIF)
- Charcot-Marie-Tooth disease, type 2R (CMT2R)
- Charcot-Marie-Tooth disease, type 2W (CMT2W)
- DRP2-associated Charcot-Marie-Tooth disease
- ATP7A-related distal hereditary motor neuropathy
- distal hereditary motor neuropathy 2A (HMN2A)
- distal hereditary motor neuropathy 2B (HMN2B)
- distal hereditary motor neuropathy 2D (HMN2D)
- distal hereditary motor neuropathy 5 (HMN5)
- distal hereditary motor neuropathy 5B (HMN5B)
- distal hereditary motor neuropathy 6 (HMN6), spinal muscular atrophy with respiratory distress 1 (SMARD1)
- distal hereditary motor neuropathy 7 (HMN7A)
- distal hereditary motor neuropathy 8 (HMN8), scapuloperoneal spinal muscular atrophy (SPSMA)
- distal hereditary motor neuropathy type VIIB (HMN7B)
- distal spinal muscular atrophy 2 (DSMA2)
- distal spinal muscular atrophy 4 (DSMA4)
- distal spinal muscular atrophy 5 (DSMA5)
- late-onset spinal muscular atrophy, Finkel type (SMAFK)
- lower extremity predominant spinal muscular atrophy 1 (SMALED1)
- polyarticular arthritis and spinal muscular atrophy, spinal muscular atrophy with progressive myoclonic epilepsy (SMAPME), Jankovic Rivera syndrome
- spinal muscular atrophy (SMA)
- spinal muscular atrophy 2 (SMAX2)
- spinal muscular atrophy with or without pontocerebellar hypoplasia type 1A (PCH1A)
- spinal muscular atrophy, Jokela type (SMAJ)
- spinal muscular atrophy, lower extremity predominant 2 (SMALED2)
- congenital insensitivity to pain with anhidrosis (CIPA), hereditary sensory and autonomic neuropathy type 4 (HSAN4)
- familial dysautonomia (FD), hereditary sensory and autonomic neuropathy type 3 (HSAN3)
- hereditary sensory and autonomic neuropathy type 1A (HSAN1A)
- hereditary sensory and autonomic neuropathy type 1C (HSAN1C)
- hereditary sensory and autonomic neuropathy type 2A (HSAN2A)
- hereditary sensory and autonomic neuropathy type 2B (HSAN2B)
- hereditary sensory and autonomic neuropathy type 2D (HSAN2D), paroxysmal extreme pain disorder (PEXPD), primary erythromelalgia, small fiber neuropathy
- hereditary sensory and autonomic neuropathy type 5 (HSAN5)
- hereditary sensory and autonomic neuropathy type 6 (HSAN6)
- hereditary sensory and autonomic neuropathy type 7 (HSAN7), familial episodic pain syndrome type 3 (FEPS3)
- hereditary sensory and autonomic neuropathy type 8 (HSAN8)
- hereditary sensory neuropathy type 1D (HSN1D)
- hereditary sensory neuropathy type 1E (HSN1E)
- hereditary sensory neuropathy type 1F (HSN1F)
- hereditary sensory neuropathy type 2C (HSN2C)
- riboflavin transporter deficiency neuronopathy, Brown-Vialetto-Van Laere syndrome 1 (BVVLS1)
- riboflavin transporter deficiency neuronopathy, Brown-Vialetto-Van Laere syndrome 2 (BVVLS2)
- amyloidosis, Finnish type
- hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis)
- APOA1-related systemic amyloidosis
- acute intermittent porphyria (AIP)
- agenesis of the corpus callosum with peripheral neuropathy (ACCPN), Andermann syndrome
- Alpers-Huttenlocher syndrome (AHS), ataxia neuropathy spectrum (ANS), childhood myocerebrohepatopathy spectrum (MCHS), myoclonic epilepsy myopathy sensory ataxia (MEMSA), progressive external ophthalmoplegia (arPEO), progressive external ophthalmoplegia with mitochondrial DNA deletions (adPEO)
- cerebrotendinous xanthomatosis (CTX)
- Fabry disease
- giant axonal neuropathy 1 (GAN1)
- hereditary motor and sensory neuropathy, Okinawa type (HMSNO)
- hereditary neuralgic amyotrophy
- hereditary neuropathy with or without age-related macular degeneration (HNARMD)
- hereditary spastic paraplegia type 5A (SPG5A)
- neuromyotonia and axonal neuropathy (NMAN)
- peripheral neuropathy, with or without impaired intellectual development (PNRIID)
- POLG2-related syndromic sensory neuropathy, progressive external ophthalmoplegia with mitochondrial deletions 4 (PEOA4)
- pontocerebellar hypoplasia type 1D (PCH1D)
- Tay-Sachs disease, beta-hexosaminidase A (HEXA) deficiency

Methodology

Targeted Exome/ Slice Exome (Next Generation Sequencing including Copy Number Variation)

Coverage

120x

Assay Information
- ATP1A1: Deletion/duplication analysis is not offered for exon 1.
- GLA: Analysis includes the intronic variant NM_000169.2:c.IVS4+919G>A.
- MME: Deletion/duplication analysis is not offered for exons 5-6.
- SCN11A: Sequencing analysis for exons 1 includes only cds +/- 10 bp.
- SMN1: Deletion/duplication analysis is not offered for exons 1-7 and sequencing analysis is not offered for this gene.; SMN1 or SMN2: The SMN1 gene is identical to the SMN2 gene with the exception of exon 8 (typically referred to as exon 7). This assay unambiguously detects SMN1 exon 8 copy number and sequence variants. Sequence variants outside of exon 8 will also be detected| but this assay cannot determine whether the variant is located in SMN1 or SMN2. SMN2 exon 8 copy number and the SMN2 exon 8 c.859G>C (p.Gly287Arg) modifier variant will be reported for individuals with a positive result in SMN1. CNVs of exons 1-7 of SMN1 or SMN2 (typically referred to as exons 1-6 in the literature) will not be reported. Variants in all exons with no evidence towards pathogenicity are not reported| but are available upon request. This assay cannot detect silent carriers (individuals that have 2 functional copies of SMN1 on one chromosome and zero copies on the other). Therefore a negative result for carrier testing greatly reduces but does not eliminate the chance that a person is a carrier. For individuals with 2 copies of SMN1| the residual risk of being a carrier has been reported to be 1 in 121 in African Americans| 1 in 345 in Ashkenazi Jewish individuals| 1 in 628 in Asians| 1 in 632 in Caucasians| and 1 in 1061 in Hispanic individuals (PMID: 23788250). The SMA-STAT test does not detect sequence variants in SMN1 or SMN2| and therefore cannot be used to identify compound heterozygotes.; SMN2: Deletion/duplication analysis is not offered for exons 1-7 and sequencing analysis is not offered for this gene.

Ordering information

Turnaround Time: 10 business days

Preferred Speciment: Saliva Kits (available upon request)

Alternate Specimens: Nail clippings or 3-mL whole blood in purple top EDTA tube

Request a specimen collection kit

Limitations

All sequencing technologies have limitations. A negative result from this analysis does not rule out a possible genetic diagnosis as some variants may not be detected by this test. This test is not designed to detect low level mosaicism, structural rearrangements, indels >40bp, deep intronic variants of unknown clinical significance, or large cytogenetic CNVs. Certain inherent qualities of the human genome, for example repetitive regions/homopolymers, GC rich, pseudogenes, and rare polymorphisms, pose significant technical challenges such as sequence misalignment that may potentially impact the accuracy of the results. False negative results may also occur in the setting of allogeneic bone marrow, stem cell transplantation, active or chronic hematologic conditions, recent blood transfusions, suboptimal DNA quality or PCR trace contamination. Other potential sources of error include sample mix-ups and clerical issues.

References
- 1. Richards S et al. Genetics in medicine. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. 2015 May;17(5):405-24 (PMID: 25741868)
- 2. GnomAD (gnomAD)
- 3. CSPEC (ClinGen variant classification rules registry) Criteria Specification Registry
- 4. Normal copy number variation in healthy individuals database of genomic variants: http://dgv.tcag.ca/dgv/app/home
- 5. Riggs, E.R., Andersen, E.F., Cherry, A.M. et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med 22, 245–257 (2020). https://doi.org/10.1038/s41436-019-0686-8
- 6. Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, Maglott DR. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 2014 Jan 1;42(1):D980-5. doi: 10.1093/nar/gkt1113. PubMed PMID: 24234437.
- 7. Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), Copyright® 1966-2012. World Wide Web URL: http://omim.org.
- 8. http://tinyurl.com/ACMGv4 (ACMG/ Clingen draft Interpretation SOP); clingen_variant-curation_sopv1.pdf

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Test Description

Associated Conditions

Methodology

Coverage

Assay Information

Ordering information

Limitations

References

Tagged Genes